Abstract PO-076: miR-181a initiates and perpetuates ovarian cancer transformation through inhibition of the tumor suppressors RB1 and stimulator of interferon genes (STING)

Abstract

Abstract Genomic instability predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high-degree of genomic instability remains unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells (FTSECs, the precursor cell type for the majority of high-grade serous ovarian cancers) through the inhibition of RB1. Increased miR-181a expression simultaneously drives cell protective inhibition of the stimulator-of-interferon-genes (STING) in order to maintain a microenvironment conducive to the propagation of cells with a high-degree of genomic instability. We found that miR-181a inhibition of RB1 leads to profound nuclear defects, genomic instability, and nuclear rupture resulting in a persistence of genomic material in the cytoplasm. Normally, this persistence of genomic material in the cytoplasm induces a cell-intrinsic interferon response through STING to drive cell death. However, miR-181a directly downregulates STING and prevents interferon induction and cell death in the FTSECs. The most common mechanism by which oncogenic miRNAs promote tumorigenesis is through the direct inhibition of tumor suppressor genes. However, our studies highlight a new mechanism of oncomiR transformation through the combination of tumor suppressor gene and intrinsic interferon signaling inhibition that initiates and propagates tumor cell survival. Importantly, we found that miR-181a induction in ovarian patient tumors is tightly associated with decreased IFNγ response and downregulation of lymphocyte infiltration and leukocyte fraction. Our findings are the first to identify a miRNA, miR-181a, that can downregulate STING expression and suppress activation of cell-intrinsic innate immune signaling in precursor cells undergoing oncogenic transformation to create a survival advantage. Our studies support the notion that the induction of STING-mediated signaling in developing cancer cells could lead directly to cancer cell death, and that these effects can be inhibited by miR-181a. Given the recent interest in the development of STING agonists as a strategy to harness the immune system to treat cancer, this study introduces miR-181a as a novel patient selective biomarker as well as potential therapeutic target for HGSOC treatment. Citation Format: Matthew Knarr, Rita Avelar, Sreeja Sekhar, Lily Kwiatkowski, Michele Dziubinski, Jessica McAnulty, Stephanie Skala, Stefanie Avril, Ronny Drapkin, Analisa DiFeo. miR-181a initiates and perpetuates ovarian cancer transformation through inhibition of the tumor suppressors RB1 and stimulator of interferon genes (STING) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-076.